CLIMACTERIC 2014;17:242–246
Premature ovarian insufficiency: how to improve reproductive outcome? J. Ben-Nagi* and N. Panay*,† *West London Menopause & PMS Centre, Chelsea and Westminster Hospital, 369 Fulham Road, London; †West London Menopause & PMS Centre, Queen Charlotte’s and Chelsea Hospital, Du Cane Road, London, UK Key words: PREMATURE OVARIAN INSUFFICIENCY, HORMONE REPLACEMENT THERAPY, CONTRACEPTIVE PILL
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ABSTRACT Premature ovarian insufficiency (POI) is a life-changing condition that affects women in their reproductive age. The condition is not necessarily permanent but is associated with intermittent and unpredictable ovarian activity. Hence, spontaneous pregnancies have been reported to be 5–10%. However, pregnancy in patients with POI is still unlikely and rare. Although, there are reviews on POI in the literature, there is a lack of reports which focus on how to improve the reproductive outcome of these women who wish to conceive spontaneously or use assisted conception with their own oocytes. We found that there is no conclusive evidence of which treatment is optimal for women with POI who wish to conceive using their own gametes. However, one could surmise that it is important to lower gonadotropin levels into the physiological range before embarking on any treatment, even if natural conception is the only choice for the woman/couple. In the future, multi-center, randomized, double-blind, placebo-controlled trials should be carried out, which may entail recruitment of patients from various centers nationally and internationally to increase the sample size and therefore achieve a powered study. This may standardize the treatment of women with POI who wish to conceive and ultimately have their biological child.
INTRODUCTION Premature ovarian insufficiency (POI) is a life-changing condition that affects women in their reproductive age. The prevalence of this condition is 1% of women younger than 40 years, 0.1% under 30 years and 0.01% under the age of 20 years1. It is associated with amenorrhea, raised gonadotropin levels and sex steroid deficiency. Common consequences are symptoms related to estrogen deficiency, infertility and psychological distress. In most cases of POI, the etiology is unknown but it can be due to autoimmune disorders, genetic diseases such as fragile X or iatrogenic (radiation, chemotherapy or surgery)2,3. The condition is not necessarily permanent like the menopause but is associated with intermittent and unpredictable ovarian activity. Hence, spontaneous pregnancies have been reported to be 5–10%4. However, pregnancy in patients with POI is still unlikely and rare. The majority of women with POI are advised that their only realistic option to conceive is to use donated gametes or embryos. This is very distressing for the women and their partners to accept that their own gametes cannot be used. They may even persuade the clinician to go ahead with assisted conception despite
being counselled that their eggs are unlikely to be retrieved or fertilized. In this review, we report on the current literature of how to improve the reproductive outcome of women with POI who wish to conceive spontaneously or by using assisted conception with their own oocytes. An electronic search was performed on PubMed and Ovid Medline from 1946 to 2012. The search terms used were (1) POI and pregnancy or ovulation induction or reproductive outcome; (2) premature ovarian failure and pregnancy or ovulation induction or reproductive outcome; (3) hypergonadotropic hypogonadism and pregnancy or ovulation induction. Despite case reports, retrospective case series and observational studies, there is a lack of randomized, controlled and powered studies in the current literature on POI and reproductive outcome with a patient’s own oocytes.
BACKGROUND There are various hypotheses that have been proposed to explain the effect of hormonal, steroid and immunosuppressive
Correspondence: Ms J. Ben-Nagi, West London Menopause & PMS Centre, Department of Gynaecology, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK; E-mail: [email protected] REVIEW © 2014 International Menopause Society DOI: 10.3109/13697137.2013.860115
Received 30-09-2013 Accepted 14-10-2013
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Premature ovarian insufficiency and reproductive outcome therapy in women with POI which may result in spontaneous or assisted conception. Estrogen per se may have a positive effect on folliculogenesis and subsequent conception. The overall goal in the use of estrogen alone or as part of hormone replacement therapy (HRT) with regards to fertility is to suppress follicle stimulating hormone (FSH) levels. HRT is thought to lower gonadotropin levels into a physiologically normal range and subsequently the FSH receptors are up-regulated5. Bidet and colleagues hypothesized that estrogen may allow restoration of FSH receptors in remnant follicles and have a direct effect on the ovaries6. This may be the likely explanation for spontaneous pregnancies achieved when HRT is commenced in women with POI7. Similarly, the combined oral contraceptive pill has been used to improve reproductive outcome in women with POI. It has been hypothesized that the suppression of endogenous raised gonadotropin levels may allow synchronized follicular growth, when the suppression is removed as the FSH levels rapidly rise8,9. Scott and Hofmann suggested that granulosa cells in women with raised FSH levels produce fewer steroids, are less viable in vitro, have a reduced mitotic index and produce lower concentrations of insulin growth factors 1 and 210. Hence, Tartagni and colleagues proposed that women with POI treated adequately may produce good quality follicles, oocytes and embryos11. Dehydroepiandrosterone (DHEA) is an endogenous steroid that is produced by the adrenal cortex and the ovarian theca cells12. Cholesterol is converted to DHEA, which is in turn important in the formation of testosterone, androstenedione and estradiol in the peripheral tissues13. The concentration of DHEA is high in the reproductive years and then diminishes with advancing age. Thus, the concentrations of testosterone, androstenedione and estradiol are low when DHEA levels fall. It has also been demonstrated that DHEA increases follicular insulin-like growth factor-1, which promotes the gonadotropin effect14. Barad and Gleicher showed that DHEA promoted the polycystic environment in the ovaries with increased levels of active oocytes and decreased atresia15. A minority of cases of POI are associated with autoimmunity and are characterized by the presence of autoantibodies against steroid-producing organs such as the thyroid, ovaries and adrenals16. The use of steroids in these cases is thought to result in immunosuppression and, in return, to improve the ovarian milieu and function6. Boumpas and colleagues hypothesized the possible role of corticosteroids in their direct antiinflammatory effect on macrophages involved in the destruction of developing follicles or their inhibitory effect on cell-mediated or humoral response17. The ovarian reserve of these follicles might be restored, which may in return result in successful ovulation induction18.
HORMONE REPLACEMENT THERAPY Case reports of spontaneous conception during or following HRT have been published in the literature. Dragojevic-Dikic and colleagues described a case of singleton pregnancy in a 33-year-old woman presenting with POI and treated with
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Ben-Nagi and Panay HRT7. Twenty months later, this therapy led to maturation of one follicle and spontaneous pregnancy ensued. A normal infant was delivered by Cesarean section. Another case study in 2006 reported on spontaneous conception 2 months after commencing HRT19. Zargar and colleagues reported three cases of women with POI, two of whom had spontaneous conceptions and the third resumed regular menstrual cycles following HRT20. These women received oral estrogen–progesterone tablets for 21 days per calendar month. Another case of an 18-year-old woman with POI who conceived spontaneously during HRT was reported by Laml and colleagues5. Elevated gonadotropin levels had returned to physiological levels whilst on hormonal treatment5.
COMBINED ORAL CONTRACEPTIVE PILL Buckler and colleagues administered Microgynon to eight women with POI for 12 weeks21. Serum FSH, luteinizing hormone (LH), estradiol, progesterone and inhibin levels were taken weekly whilst on treatment. In addition to blood sampling, ovarian ultrasonography was carried out to monitor follicular growth on stopping Microgynon. After 5 weeks of treatment, FSH and LH levels declined to the follicular-phase range. However, both gonadotropin levels rapidly rose after stopping treatment and were above the normal follicular levels by the first week. Serum estradiol and inhibin levels were undetectable throughout the study. Furthermore, follicular growth was not seen on ultrasound scan. The authors concluded that resumption of follicular growth does not occur when serum gonadotropin levels are suppressed by the combined oral contraceptive pill in women with POI. Ethinylestradiol has also been used in the treatment of POI to induce ovulation and subsequent pregnancy. The most recent published study by Tartagni and colleagues was to evaluate pretreatment with ethinylestradiol in women with POI22. This was a double-blind, placebo-controlled, randomized trial in 50 women with POI seeking pregnancy. The intervention group received 0.05 mg ethinylestradiol three times a day for 2 weeks pre-stimulation and the second group received placebo. Ovarian stimulation was carried out using recombinant FSH (200 IU/day subcutaneously) and human chorionic gonadotropin was administered once the follicle exceeded 18 mm in diameter. Ethinylestradiol and placebo were given during ovarian stimulation. FSH levels were significantly lower in the intervention group than in the placebo group, whilst the ovulation rate was significantly higher in the study group (32%) than in the control group (0%). Tartagni and colleagues showed the efficiency of hormonal treatment to improve fertility in women with POI22. The authors highlighted that FSH ⬍ ⫺ 15 mIU/ml should be achieved before commencing ovarian stimulation. Tartagni and colleagues have also reported on oocyte and embryo quality in a 34-year-old woman with POI after pretreatment with ethinylestradiol (0.05 mg three times per day) followed by ethinylestradiol in conjunction with ovarian
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Premature ovarian insufficiency and reproductive outcome stimulation using gonadotropins11. The two oocytes retrieved were well developed and metaphase II had been reached. Their morphology was normal once the oocytes were denuded. On day 2 post-fertilization, the embryos were judged to be of grade 1. A clinical pregnancy was confirmed on ultrasound at 6 weeks’ gestation.
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GONADOTROPIN RELEASING HORMONE AGONIST Gonadotropin releasing agonists (GnRHa) have been described in some studies to induce ovulation by lowering elevated gonadotropin levels. The current literature lacks randomized and adequately powered studies to detect any significant difference in ovulation induction and pregnancy rates. In one of the subgroup of six patients with POI who underwent gonadotropin suppression with GnRHa therapy followed by concomitant human menopausal gonadotropin stimulation23, ovulation occurred in only one patient (17%) and pregnancy did not ensue. Nelson and collegues carried out a prospective, doubleblind, placebo-controlled trial for the treatment of karyotypically normal women with spontaneous POI24. The intervention arm of the trial consisted of 23 women receiving daily subcutaneous injection of 300 μg GnRHa. Both groups took a standardized estrogen replacement regimen. They found GnRHa therapy did not significantly enhance the chance of ovulation (13% vs. 9%) or conception (one pregnancy in the intervention arm). In another placebo-controlled, randomized, double-blind study of 30 patients, only three of the 15 patients in the agonist group ovulated versus none in the placebo-treated group25. The study demonstrated that pituitary suppression with GnRHa does not improve the success of ovulation and conception in women with POI.
GONADOTROPIN RELEASING HORMONE ANTAGONIST Gonadotropin releasing hormone antagonist is rarely used to induce ovulation and pregnancy in women with POI. To the best of our knowledge, there is only one case report in the literature describing ovulation induction and pregnancy in a woman with POI following cetrolix26. Gonadotropin suppression was achieved using cetrolix in a 37-year-old woman with POI. As FSH levels dropped, serum estradiol levels rose to 200 pg/ml after 10 days of Cetrotide. She conceived spontaneously in the same cycle and a viable ongoing pregnancy was demonstrated on ultrasound scan. Further studies are required in the use of gonadotropin releasing hormone antagonist in women with POI.
GONADOTROPINS The use of gonadotropins alone in ovulation induction in women with POI is scarce in the current literature. Rosen
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Ben-Nagi and Panay and colleagues studied ovulation induction with gonadotropins in eight women with POI27. These patients were treated with GnRHa alone in one treatment cycle and the same analog plus human menopausal gonadotropins in the subsequent treatment cycle. Two women ovulated in each group. The authors concluded that women with POI can ovulate but inadequate secretion of luteal-phase progesterone is likely to occur. The pregnancy rate was not reported in the study. In another study, two subgroups of women with POF had ovulation induction attempted. One group had estrogen-induced suppression followed by human menopausal gonadotropin stimulation (n ⫽ 4) and the second group had estrogen-induced suppression followed by human menopausal gonadotropin stimulation with concomitant estrogen therapy (n ⫽ 10)23. Ovulation did not occur in either group despite complete gonadotropin suppression and high-dose human menopausal gonadotropin therapy. The use of gonadotropin alone in the treatment of patients with POI is rare as its use may be deleterious due to the expression of auto-antigens on the ovarian granulosa cells28.
CLOMIPHENE CITRATE There is a lack of randomized control studies in the current literature on the use of clomiphene citrate in women with POI. Davis and Ravnikar reported on successful ovulation induction in woman with POF using high-dose clomiphene citrate in combination with prednisolone and oral micronized 17β-estradiol29, whilst Nakai and colleagues described a 28-year-old woman with POI who conceived after clomiphene citrate30. It is arguable whether conception might have occurred irrespective of clomiphene citrate but as a result of intermittent ovarian function in these two case reports. It should be highlighted that clomiphene citrate needs basal estrogen to be able to act on the pituitary31. In normoestrogenic women and under GnRH stimulation, clomiphene promotes FSH release with a predominant inhibitory effect on LH release31. Thus, clomiphene citrate used in cases of POI is unlikely to be successful in ovulation induction in view of the women’s hypoestrogenic state.
STEROIDS Immunosuppressive treatment such as corticosteroids has been used in ovulation induction in idiopathic POI18. The study consisted of 58 women with idiopathic POI who were randomly allocated to either GnRHa plus gonadotropin therapy and corticosteroids versus GnRHa plus gonadotropin and placebo18. Ovulation occurred in 21% of the cases in the corticosteroid group compared to 10% in the placebo group. There were two singleton pregnancies in the intervention group. The authors concluded that a combination of pituitary suppression and corticosteroids can restore ovulation in women with idiopathic POI.
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Premature ovarian insufficiency and reproductive outcome However, another randomized study compared the effect of dexamethasone versus placebo on ovarian responsiveness to exogenous gonadotropins in patients with idiopathic premature ovarian failure32. The study showed that steroids did not influence ovarian response to gonadotropins and subsequent ovulation rate. It should be borne in mind that most studies are small and therefore not sufficiently powerful to reach statistical significance. Furthermore, documentation of idiopathic versus autoimmune POI is suboptimal as treatment is likely to differ depending on the cause of the disease. Furthermore, steroids are associated with major complications such as iatrogenic Cushing’s, diabetes and osteonecrosis. Hence, only identified cases with autoimmune POI should be offered immune modulation therapy33.
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DEHYDROEPIANDROSTERONE In 2009, Mamas and Mamas published the first case studies of five women with POI who received 50–75 μg DHEA13. The duration of the treatment was between 1 and 6 months. PostDHEA treatment, the FSH levels dropped and all the cases conceived spontaneously. One patient had a live birth delivered by Cesarean section, one case had a missed miscarriage and three cases had ongoing pregnancies. Fourteen more women with POI have been recruited to the case series of Mamas and Mamas (2009)34. The women’s FSH varied between 62 and 98 mIU/ml and presented with 6–9 months of amenorrhea. Natural conception occurred in eight women within 3–7 months of therapy. The remaining six women did not conceive following 6 months of DHEA. Five of the six cases had FSH levels ⬎ 40 mIU/ml which were likely to be due to bilateral ovarian surgery for endometriosis34. It could be argued that those who did conceive may have been as a result of intermittent ovarian activity which, as previously mentioned, occurs in women with POI aged ⬍ 40 years. The remaining sixth case had idiopathic POI and did not respond to DHEA therapy. DHEA has been widely used in women with POI or reduced ovarian reserve and poor responders to ovarian stimulation. Some authors have advocated its use to increase the number of oocytes retrieved in assisted conception cycles, improve pregnancy rates and decrease miscarriage rates34. The latest randomized, double-blind, placebo-controlled trial assessed the efficacy of DHEA on ovarian reserve markers in women with POI35. The intervention arm consisted of ten subjects who received DHEA (25 mg three times a day) and the control group (n ⫽ 12) received placebo for 16 weeks. Serum anti-Müllerian
Ben-Nagi and Panay hormone and FSH levels were not significantly different between the two groups. However, antral follicle count, ovarian volume, testosterone, DHEA sulfate and estradiol levels were significantly higher in the intervention group. A larger randomized study with longer duration of DHEA therapy is required to assess the efficacy of DHEA in women with POI in relation to their overall well-being as well as their reproductive outcome.
CONCLUSIONS POI is a heterogeneous condition. The cause in the majority of cases is idiopathic. As a result of its heterogeneity and rarity, most published data consist of small numbers of retrospective case series or reports. Even when randomized studies are published, they are underpowered to detect any statistical significance. There is no conclusive evidence of which treatment is optimal for women with POI who wish to conceive using their own gametes. However, one could surmise that it is important to lower gonadotropin levels into the physiological range before embarking on any treatment, even if natural conception is the only choice for the woman/couple. In the future, multi-center, randomized, double-blind, placebo-controlled trials should be carried out, which may entail recruitment of patients from various centers nationally and internationally to increase the sample size and therefore achieve a powered study. This will, in turn, allow development of protocols and pathways in order to treat women with POI who wish to conceive and have their biological child. As there is a lack of prospective, randomized, controlled trials, high-quality observational data are required to formulate evidence-based guidelines for diagnosis and management. We have already established a database of our cohort of 450 cases over a number of years36. A number of international experts have agreed to contribute to this database37. Furthermore, real-time data entry will be commenced in 2013 once international collaborators have given their views on the structure of the database37. There will be limitations to this data registry but ultimately it will provide a consensus to improve and standardize patient care nationally and internationally. Conflict of interest The authors report no confl ict of interest. The authors alone are responsible for the content and writing of this paper. Source of funding
Nil.
References 1. Coulam C, Adamson S, Annegers J. Incidence of premature ovarian failure. Obstet Gynecol 1986;67:604–6 2. Kalu E, Panay N. Spontaneous premature ovarian failure: management challenges. Gynecol Endocrinol 2008;24:273–9 3. Fogli A, Rodriguez D, Eymard-Pierre E, et al. Ovarian failure related to eukaryotic initiation factor 2B mutations. Am J Hum Genet 2003;72:1544–50
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4. Van Kasteren Y, Schoemaker J. Premature ovarian failure: a systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy. Hum Reprod Update 1999;5:483–92 5. Laml T, Huber J, Albrecht A, Sintenis W, Hartmann B. Unexpected pregnancy during hormone replacement therapy in a woman with elevated follicle stimulating hormone levels and amenorrhea. Gynecol Endocrinol 1999;13:89–92
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Premature ovarian insufficiency and reproductive outcome 6. Bidet M, Bachelot A, Touraine P. Premature ovarian failure: predictability of intermittent ovarian function and response to ovulation induction agents. Curr Opin Obstet Gynecol 2008; 20:416–20 7. Dragojevic-Dikic S, Rakic S, Nikolic B, Popovac S. Hormone replacement therapy and successful pregnancy in a patient with premature ovarian failure. Gynecol Endocrinol 2009;25:769–72 8. Alper M, Joly E, Garner P. Pregnancies after premature ovarian failure. Obstet Gynecol 1986;67:59–62S 9. Check J, Chase J, Spence M. Pregnancy in premature ovarian failure after therapy with oral contraceptives despite resistance to previous human menopausal gonadotropin therapy. Am J Obstet Gynecol 1989;160:114–15 10. Scott R, Hofmann G. Prognostic assessment of ovarian reserve. Fertil Steril 1995;63:1–11 11. Tartagni M, Damiani G, Di Naro E, Persiani P, Crescini C, Loverro G. Pregnancy in a woman with premature ovarian insufficiency undergoing intracytoplasmic sperm injection after pretreatment with estrogens followed by therapy with estrogens associated with ovarian stimulation with gonadotropins: results about oocyte & embryo quality. Menopause 2011;18:932–4 12. Burger H. Androgen production in women. Fertil Steril 2002; 77:S3–5 13. Mamas L, Mamas E. Premature ovarian failure and dehydroepiandrosterone. Fertil Steril 2009;91:644–6 14. Casson P, Lindsay M, Pisarska M, Carson S, Buster J. Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders: a case series. Hum Reprod 2000;15:2129–32 15. Barad D, Gleicher N. Increased oocyte production after treatment with dehydroepiandrosterone. Fertil Steril 2005;84:756 16. Hoek A, Schoemaker J, Drexhage H. Premature ovarian failure and ovarian autoimmunity. Endocrine Rev 1997;18:107–34 17. Boumpas D. Chrousos G, Wilder R, Cupps T, Balow J. Glucocorticoid therapy for immune-mediated diseases: basic and clinical correlates. Ann Intern Med 1993;119:1198–208 18. Badawy A, Goda H, Ragab A. Induction of ovulation in idiopathic premature ovarian failure: a randomized double blind trial. Reprod Biomed Online 2007;15:215–19 19. Vandborg M, Lauszus F. Premature ovarian failure and pregnancy. Arch Gynecol Obstet 2006;273:387–8 20. Zargar A, Salahuddin M, Wani A, Bashir M, Masoodi S, Laway B. Pregnancy in premature ovarian failure: a possible role of estrogen plus progesterone treatment. J Assoc Physicians India 2000;48:213–15 21. Buckler H, Healy D, Burger H. Does gonadotropin suppression result in follicular development in premature ovarian failure? Gynaecol Endocrinol 1993;7:123–8 22. Tartagni M, Cicinelli E, De Pergola G, De Salvia M, Lavopa C, Loverro G. Effects of pretreatment with estrogens on ovarian stimulation with gonadotropins in women with premature ovarian failure: a randomized, placebo controlled trial. Fertil Steril 2007;87:858–61
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Ben-Nagi and Panay 23. Surrey E, Cedars M. The effect of gonadotropin suppression on the induction of ovulation in premature ovarian failure patients. Fertil Steril 1989;52:36–41 24. Nelson L, Kimzey L, White B, Merriam G. Gonadotropin suppression for the treatment of karyotypically normal spontaneous premature ovarian failure: a controlled trial. Fertil Steril 1992; 57:50–5 25. Van Kasteren Y, Hoek A, Schoemaker J. Ovulation induction in premature ovarian failure: a placebo-controlled randomized trial combining pituitary suppression with gonadotropin stimulation. Fertil Steril 1995;64:273–8 26. Check J, Katsoff B. Ovulation induction and pregnancy in a woman with premature menopause following gonadotropin suppression with the gonadotropin releasing hormone antagonist, cetrolix – a case report. Clin Exp Obstet Gynecol 2008;35: 10–12 27. Rosen G, Stone S, Yee B. Ovulation induction in women with premature ovarian failure: a prospective, crossover study. Fertil Steril 1992;57:448–9 28. Tidey G, Nelson L, Phillips T, Stillman R. Gonadotropins enhance HLA-DR antigen expression in human granulosa cells. Am J Obset Gynecol 1992;167:1768–73 29. Davis O, Ravnikar V. Ovulation induction with clomiphene citrate in a woman with premature ovarian failure. A case report. J Reprod Med 1988;33:559–62 30. Nakai M, Tatsumi H, Arai M. Case report. Successive pregnancies in a patient with premature ovarian failure. Eur J Obstet Gynecol Reprod Biol 1984;18:217–24 31. De Moura M, Ferriani R, De Sa M. Effects of clomiphene citrate on pituitary luteinizing hormone and follicle-stimulating hormone release in women before and after treatment with ethinyl oestradiol. Fertil Steril 1992;58:504–7 32. Van Kasteren Y, Braat D, Hemrika D, et al. Corticosteroids do not influence ovarian responsiveness to gonadotropins in patients with premature ovarian failure: a randomized, placebo-controlled trial. Fertil Steril 1999;71:90–5 33. Kalantaridou S, Braddock D, Patronas N, Nelson L. Treatment of autoimmune premature ovarian failure. Hum Reprod 1999; 14:1777–82 34. Mamas L, Mamas E. Dehydroepiandrosterone supplementation in assisted reproduction: rationale and results. Curr Opin Obstet Gynecol 2009;21:306–8 35. Yeung T, Li R, Lee V, Ho P, Ng E. A randomized double-blinded placebo-controlled trial on the effect of dehydroepiandrosterone for 16 weeks on ovarian response markers in women with primary ovarian insufficiency. J Clin Endocrinol Metab 2013;98: 380–8 36. Maclaran K, Panay N. Presentation and management of POF: Findings from the West London POF database. Presented at 15th World Congress of Gynecological Endocrinology, Florence, Italy, March, 2012 37. Panay N, Fenton A. Premature ovarian insufficiency: working towards an international database. Climacteric 2012;15:295–6
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Premature ovarian insufficiency: how to improve reproductive outcome? J. Ben-Nagi* and N. Panay*,† *West London Menopause & PMS Centre, Chelsea and Westminster Hospital, 369 Fulham Road, London; †West London Menopause & PMS Centre, Queen Charlotte’s and Chelsea Hospital, Du Cane Road, London, UK Key words: PREMATURE OVARIAN INSUFFICIENCY, HORMONE REPLACEMENT THERAPY, CONTRACEPTIVE PILL
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ABSTRACT Premature ovarian insufficiency (POI) is a life-changing condition that affects women in their reproductive age. The condition is not necessarily permanent but is associated with intermittent and unpredictable ovarian activity. Hence, spontaneous pregnancies have been reported to be 5–10%. However, pregnancy in patients with POI is still unlikely and rare. Although, there are reviews on POI in the literature, there is a lack of reports which focus on how to improve the reproductive outcome of these women who wish to conceive spontaneously or use assisted conception with their own oocytes. We found that there is no conclusive evidence of which treatment is optimal for women with POI who wish to conceive using their own gametes. However, one could surmise that it is important to lower gonadotropin levels into the physiological range before embarking on any treatment, even if natural conception is the only choice for the woman/couple. In the future, multi-center, randomized, double-blind, placebo-controlled trials should be carried out, which may entail recruitment of patients from various centers nationally and internationally to increase the sample size and therefore achieve a powered study. This may standardize the treatment of women with POI who wish to conceive and ultimately have their biological child.
INTRODUCTION Premature ovarian insufficiency (POI) is a life-changing condition that affects women in their reproductive age. The prevalence of this condition is 1% of women younger than 40 years, 0.1% under 30 years and 0.01% under the age of 20 years1. It is associated with amenorrhea, raised gonadotropin levels and sex steroid deficiency. Common consequences are symptoms related to estrogen deficiency, infertility and psychological distress. In most cases of POI, the etiology is unknown but it can be due to autoimmune disorders, genetic diseases such as fragile X or iatrogenic (radiation, chemotherapy or surgery)2,3. The condition is not necessarily permanent like the menopause but is associated with intermittent and unpredictable ovarian activity. Hence, spontaneous pregnancies have been reported to be 5–10%4. However, pregnancy in patients with POI is still unlikely and rare. The majority of women with POI are advised that their only realistic option to conceive is to use donated gametes or embryos. This is very distressing for the women and their partners to accept that their own gametes cannot be used. They may even persuade the clinician to go ahead with assisted conception despite
being counselled that their eggs are unlikely to be retrieved or fertilized. In this review, we report on the current literature of how to improve the reproductive outcome of women with POI who wish to conceive spontaneously or by using assisted conception with their own oocytes. An electronic search was performed on PubMed and Ovid Medline from 1946 to 2012. The search terms used were (1) POI and pregnancy or ovulation induction or reproductive outcome; (2) premature ovarian failure and pregnancy or ovulation induction or reproductive outcome; (3) hypergonadotropic hypogonadism and pregnancy or ovulation induction. Despite case reports, retrospective case series and observational studies, there is a lack of randomized, controlled and powered studies in the current literature on POI and reproductive outcome with a patient’s own oocytes.
BACKGROUND There are various hypotheses that have been proposed to explain the effect of hormonal, steroid and immunosuppressive
Correspondence: Ms J. Ben-Nagi, West London Menopause & PMS Centre, Department of Gynaecology, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK; E-mail: [email protected] REVIEW © 2014 International Menopause Society DOI: 10.3109/13697137.2013.860115
Received 30-09-2013 Accepted 14-10-2013
Climacteric Downloaded from informahealthcare.com by Nyu Medical Center on 04/18/15 For personal use only.
Premature ovarian insufficiency and reproductive outcome therapy in women with POI which may result in spontaneous or assisted conception. Estrogen per se may have a positive effect on folliculogenesis and subsequent conception. The overall goal in the use of estrogen alone or as part of hormone replacement therapy (HRT) with regards to fertility is to suppress follicle stimulating hormone (FSH) levels. HRT is thought to lower gonadotropin levels into a physiologically normal range and subsequently the FSH receptors are up-regulated5. Bidet and colleagues hypothesized that estrogen may allow restoration of FSH receptors in remnant follicles and have a direct effect on the ovaries6. This may be the likely explanation for spontaneous pregnancies achieved when HRT is commenced in women with POI7. Similarly, the combined oral contraceptive pill has been used to improve reproductive outcome in women with POI. It has been hypothesized that the suppression of endogenous raised gonadotropin levels may allow synchronized follicular growth, when the suppression is removed as the FSH levels rapidly rise8,9. Scott and Hofmann suggested that granulosa cells in women with raised FSH levels produce fewer steroids, are less viable in vitro, have a reduced mitotic index and produce lower concentrations of insulin growth factors 1 and 210. Hence, Tartagni and colleagues proposed that women with POI treated adequately may produce good quality follicles, oocytes and embryos11. Dehydroepiandrosterone (DHEA) is an endogenous steroid that is produced by the adrenal cortex and the ovarian theca cells12. Cholesterol is converted to DHEA, which is in turn important in the formation of testosterone, androstenedione and estradiol in the peripheral tissues13. The concentration of DHEA is high in the reproductive years and then diminishes with advancing age. Thus, the concentrations of testosterone, androstenedione and estradiol are low when DHEA levels fall. It has also been demonstrated that DHEA increases follicular insulin-like growth factor-1, which promotes the gonadotropin effect14. Barad and Gleicher showed that DHEA promoted the polycystic environment in the ovaries with increased levels of active oocytes and decreased atresia15. A minority of cases of POI are associated with autoimmunity and are characterized by the presence of autoantibodies against steroid-producing organs such as the thyroid, ovaries and adrenals16. The use of steroids in these cases is thought to result in immunosuppression and, in return, to improve the ovarian milieu and function6. Boumpas and colleagues hypothesized the possible role of corticosteroids in their direct antiinflammatory effect on macrophages involved in the destruction of developing follicles or their inhibitory effect on cell-mediated or humoral response17. The ovarian reserve of these follicles might be restored, which may in return result in successful ovulation induction18.
HORMONE REPLACEMENT THERAPY Case reports of spontaneous conception during or following HRT have been published in the literature. Dragojevic-Dikic and colleagues described a case of singleton pregnancy in a 33-year-old woman presenting with POI and treated with
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Ben-Nagi and Panay HRT7. Twenty months later, this therapy led to maturation of one follicle and spontaneous pregnancy ensued. A normal infant was delivered by Cesarean section. Another case study in 2006 reported on spontaneous conception 2 months after commencing HRT19. Zargar and colleagues reported three cases of women with POI, two of whom had spontaneous conceptions and the third resumed regular menstrual cycles following HRT20. These women received oral estrogen–progesterone tablets for 21 days per calendar month. Another case of an 18-year-old woman with POI who conceived spontaneously during HRT was reported by Laml and colleagues5. Elevated gonadotropin levels had returned to physiological levels whilst on hormonal treatment5.
COMBINED ORAL CONTRACEPTIVE PILL Buckler and colleagues administered Microgynon to eight women with POI for 12 weeks21. Serum FSH, luteinizing hormone (LH), estradiol, progesterone and inhibin levels were taken weekly whilst on treatment. In addition to blood sampling, ovarian ultrasonography was carried out to monitor follicular growth on stopping Microgynon. After 5 weeks of treatment, FSH and LH levels declined to the follicular-phase range. However, both gonadotropin levels rapidly rose after stopping treatment and were above the normal follicular levels by the first week. Serum estradiol and inhibin levels were undetectable throughout the study. Furthermore, follicular growth was not seen on ultrasound scan. The authors concluded that resumption of follicular growth does not occur when serum gonadotropin levels are suppressed by the combined oral contraceptive pill in women with POI. Ethinylestradiol has also been used in the treatment of POI to induce ovulation and subsequent pregnancy. The most recent published study by Tartagni and colleagues was to evaluate pretreatment with ethinylestradiol in women with POI22. This was a double-blind, placebo-controlled, randomized trial in 50 women with POI seeking pregnancy. The intervention group received 0.05 mg ethinylestradiol three times a day for 2 weeks pre-stimulation and the second group received placebo. Ovarian stimulation was carried out using recombinant FSH (200 IU/day subcutaneously) and human chorionic gonadotropin was administered once the follicle exceeded 18 mm in diameter. Ethinylestradiol and placebo were given during ovarian stimulation. FSH levels were significantly lower in the intervention group than in the placebo group, whilst the ovulation rate was significantly higher in the study group (32%) than in the control group (0%). Tartagni and colleagues showed the efficiency of hormonal treatment to improve fertility in women with POI22. The authors highlighted that FSH ⬍ ⫺ 15 mIU/ml should be achieved before commencing ovarian stimulation. Tartagni and colleagues have also reported on oocyte and embryo quality in a 34-year-old woman with POI after pretreatment with ethinylestradiol (0.05 mg three times per day) followed by ethinylestradiol in conjunction with ovarian
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Premature ovarian insufficiency and reproductive outcome stimulation using gonadotropins11. The two oocytes retrieved were well developed and metaphase II had been reached. Their morphology was normal once the oocytes were denuded. On day 2 post-fertilization, the embryos were judged to be of grade 1. A clinical pregnancy was confirmed on ultrasound at 6 weeks’ gestation.
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GONADOTROPIN RELEASING HORMONE AGONIST Gonadotropin releasing agonists (GnRHa) have been described in some studies to induce ovulation by lowering elevated gonadotropin levels. The current literature lacks randomized and adequately powered studies to detect any significant difference in ovulation induction and pregnancy rates. In one of the subgroup of six patients with POI who underwent gonadotropin suppression with GnRHa therapy followed by concomitant human menopausal gonadotropin stimulation23, ovulation occurred in only one patient (17%) and pregnancy did not ensue. Nelson and collegues carried out a prospective, doubleblind, placebo-controlled trial for the treatment of karyotypically normal women with spontaneous POI24. The intervention arm of the trial consisted of 23 women receiving daily subcutaneous injection of 300 μg GnRHa. Both groups took a standardized estrogen replacement regimen. They found GnRHa therapy did not significantly enhance the chance of ovulation (13% vs. 9%) or conception (one pregnancy in the intervention arm). In another placebo-controlled, randomized, double-blind study of 30 patients, only three of the 15 patients in the agonist group ovulated versus none in the placebo-treated group25. The study demonstrated that pituitary suppression with GnRHa does not improve the success of ovulation and conception in women with POI.
GONADOTROPIN RELEASING HORMONE ANTAGONIST Gonadotropin releasing hormone antagonist is rarely used to induce ovulation and pregnancy in women with POI. To the best of our knowledge, there is only one case report in the literature describing ovulation induction and pregnancy in a woman with POI following cetrolix26. Gonadotropin suppression was achieved using cetrolix in a 37-year-old woman with POI. As FSH levels dropped, serum estradiol levels rose to 200 pg/ml after 10 days of Cetrotide. She conceived spontaneously in the same cycle and a viable ongoing pregnancy was demonstrated on ultrasound scan. Further studies are required in the use of gonadotropin releasing hormone antagonist in women with POI.
GONADOTROPINS The use of gonadotropins alone in ovulation induction in women with POI is scarce in the current literature. Rosen
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Ben-Nagi and Panay and colleagues studied ovulation induction with gonadotropins in eight women with POI27. These patients were treated with GnRHa alone in one treatment cycle and the same analog plus human menopausal gonadotropins in the subsequent treatment cycle. Two women ovulated in each group. The authors concluded that women with POI can ovulate but inadequate secretion of luteal-phase progesterone is likely to occur. The pregnancy rate was not reported in the study. In another study, two subgroups of women with POF had ovulation induction attempted. One group had estrogen-induced suppression followed by human menopausal gonadotropin stimulation (n ⫽ 4) and the second group had estrogen-induced suppression followed by human menopausal gonadotropin stimulation with concomitant estrogen therapy (n ⫽ 10)23. Ovulation did not occur in either group despite complete gonadotropin suppression and high-dose human menopausal gonadotropin therapy. The use of gonadotropin alone in the treatment of patients with POI is rare as its use may be deleterious due to the expression of auto-antigens on the ovarian granulosa cells28.
CLOMIPHENE CITRATE There is a lack of randomized control studies in the current literature on the use of clomiphene citrate in women with POI. Davis and Ravnikar reported on successful ovulation induction in woman with POF using high-dose clomiphene citrate in combination with prednisolone and oral micronized 17β-estradiol29, whilst Nakai and colleagues described a 28-year-old woman with POI who conceived after clomiphene citrate30. It is arguable whether conception might have occurred irrespective of clomiphene citrate but as a result of intermittent ovarian function in these two case reports. It should be highlighted that clomiphene citrate needs basal estrogen to be able to act on the pituitary31. In normoestrogenic women and under GnRH stimulation, clomiphene promotes FSH release with a predominant inhibitory effect on LH release31. Thus, clomiphene citrate used in cases of POI is unlikely to be successful in ovulation induction in view of the women’s hypoestrogenic state.
STEROIDS Immunosuppressive treatment such as corticosteroids has been used in ovulation induction in idiopathic POI18. The study consisted of 58 women with idiopathic POI who were randomly allocated to either GnRHa plus gonadotropin therapy and corticosteroids versus GnRHa plus gonadotropin and placebo18. Ovulation occurred in 21% of the cases in the corticosteroid group compared to 10% in the placebo group. There were two singleton pregnancies in the intervention group. The authors concluded that a combination of pituitary suppression and corticosteroids can restore ovulation in women with idiopathic POI.
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Premature ovarian insufficiency and reproductive outcome However, another randomized study compared the effect of dexamethasone versus placebo on ovarian responsiveness to exogenous gonadotropins in patients with idiopathic premature ovarian failure32. The study showed that steroids did not influence ovarian response to gonadotropins and subsequent ovulation rate. It should be borne in mind that most studies are small and therefore not sufficiently powerful to reach statistical significance. Furthermore, documentation of idiopathic versus autoimmune POI is suboptimal as treatment is likely to differ depending on the cause of the disease. Furthermore, steroids are associated with major complications such as iatrogenic Cushing’s, diabetes and osteonecrosis. Hence, only identified cases with autoimmune POI should be offered immune modulation therapy33.
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DEHYDROEPIANDROSTERONE In 2009, Mamas and Mamas published the first case studies of five women with POI who received 50–75 μg DHEA13. The duration of the treatment was between 1 and 6 months. PostDHEA treatment, the FSH levels dropped and all the cases conceived spontaneously. One patient had a live birth delivered by Cesarean section, one case had a missed miscarriage and three cases had ongoing pregnancies. Fourteen more women with POI have been recruited to the case series of Mamas and Mamas (2009)34. The women’s FSH varied between 62 and 98 mIU/ml and presented with 6–9 months of amenorrhea. Natural conception occurred in eight women within 3–7 months of therapy. The remaining six women did not conceive following 6 months of DHEA. Five of the six cases had FSH levels ⬎ 40 mIU/ml which were likely to be due to bilateral ovarian surgery for endometriosis34. It could be argued that those who did conceive may have been as a result of intermittent ovarian activity which, as previously mentioned, occurs in women with POI aged ⬍ 40 years. The remaining sixth case had idiopathic POI and did not respond to DHEA therapy. DHEA has been widely used in women with POI or reduced ovarian reserve and poor responders to ovarian stimulation. Some authors have advocated its use to increase the number of oocytes retrieved in assisted conception cycles, improve pregnancy rates and decrease miscarriage rates34. The latest randomized, double-blind, placebo-controlled trial assessed the efficacy of DHEA on ovarian reserve markers in women with POI35. The intervention arm consisted of ten subjects who received DHEA (25 mg three times a day) and the control group (n ⫽ 12) received placebo for 16 weeks. Serum anti-Müllerian
Ben-Nagi and Panay hormone and FSH levels were not significantly different between the two groups. However, antral follicle count, ovarian volume, testosterone, DHEA sulfate and estradiol levels were significantly higher in the intervention group. A larger randomized study with longer duration of DHEA therapy is required to assess the efficacy of DHEA in women with POI in relation to their overall well-being as well as their reproductive outcome.
CONCLUSIONS POI is a heterogeneous condition. The cause in the majority of cases is idiopathic. As a result of its heterogeneity and rarity, most published data consist of small numbers of retrospective case series or reports. Even when randomized studies are published, they are underpowered to detect any statistical significance. There is no conclusive evidence of which treatment is optimal for women with POI who wish to conceive using their own gametes. However, one could surmise that it is important to lower gonadotropin levels into the physiological range before embarking on any treatment, even if natural conception is the only choice for the woman/couple. In the future, multi-center, randomized, double-blind, placebo-controlled trials should be carried out, which may entail recruitment of patients from various centers nationally and internationally to increase the sample size and therefore achieve a powered study. This will, in turn, allow development of protocols and pathways in order to treat women with POI who wish to conceive and have their biological child. As there is a lack of prospective, randomized, controlled trials, high-quality observational data are required to formulate evidence-based guidelines for diagnosis and management. We have already established a database of our cohort of 450 cases over a number of years36. A number of international experts have agreed to contribute to this database37. Furthermore, real-time data entry will be commenced in 2013 once international collaborators have given their views on the structure of the database37. There will be limitations to this data registry but ultimately it will provide a consensus to improve and standardize patient care nationally and internationally. Conflict of interest The authors report no confl ict of interest. The authors alone are responsible for the content and writing of this paper. Source of funding
Nil.
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